The major focus of the laboratory this year has continued to be on multidrug resistance mediated by the drug efflux pump, P-glycoprotein (Pgp), although we have begun to characterize other mechanisms of resistance as well. Studies of P-glycoprotein have been directed toward understanding the role that protein kinase C plays in regulating function. While activation of PKC increases Pgp phosphorylation and function, down regulation of PKC may not result in inhibition of function. Studies have continued toward understanding the role that P-glycoprotein plays in clinical drug resistance in lymphoma. Patient samples analyzed for mdr-1 expression have demonstrated increased levels after treatment failure. Extensive laboratory studies validated our approach to measurement of mdr- 1 in the patient samples. Our clinical study of Pgp reversal, a Phase 1 study utilizing PSC 833 as Pgp antagonist, opened in February and has accrued 10 patients. A second project involves study of non-Pgp mediated drug resistance in breast cancer. Studies have continued toward understanding growth factor and receptor alterations which occur with the onset of drug resistance in human breast cancer cells in culture. The goal of this work is to find a target for interruption of signal transduction from these receptors that will prevent the development of chemoresistance. In addition, we have begun to isolate the mechanism of drug resistance in MCF-7/Adrvp cells, a breast cancer subline which is doxorubicin resistant, does not express Pgp, is not sensitized by verapamil, and overexpresses a 95 kDa protein on the cell surface.